PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway

Abstract

As immune checkpoint inhibitors (ICIs) continue to advance, more evidence has emerged that anti-PD-1/PD-L1 immunotherapy is an effective treatment against cancers. Known as the programmed death ligand-1 (PD-L1), this co-inhibitory ligand contributes to T cell exhaustion by interacting with programmed death-1 (PD-1) receptor. However, cancer-intrinsic signaling pathways of the PD-L1 molecule are not well elucidated. Therefore, the present study aimed to evaluate the regulatory network of PD-L1 and lay the basis of successful use of anti-PD-L1 immunotherapy in acute myeloid leukemia (AML). Data for AML patients were extracted from TCGA and GTEx databases. The downstream signaling pathways of PD-L1 were identified via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The key PD-L1 related genes were selected by weighted gene co-expression network analysis (WGCNA), MCC algorithm and Molecular Complex Detection (MCODE). The CCK-8 assay was used to assess cell proliferation. Flow cytometry was used to determine cell apoptosis and cell cycle. Western blotting was used to identify the expression of the PI3K-AKT signaling pathway. PD-L1 was shown to be elevated in AML patients when compared with the control group, and high PD-L1 expression was associated with poor overall survival rate. The ECM-receptor interaction, as well as the PI3K-AKT signaling pathway, were important PD-L1 downstream pathways. All three analyses found eight genes (ITGA2B, ITGB3, COL6A5, COL6A6, PF4, NMU, AGTR1, F2RL3) to be significantly associated with PD-L1. Knockdown of PD-L1 inhibited AML cell proliferation, induced cell apoptosis and G2/M cell cycle arrest. Importantly, PD-L1 knockdown reduced the expression of PI3K and p-AKT, but PD-L1 overexpression increased their expression. The current study elucidates the main regulatory network and downstream targets of PD-L1 in AML, assisting in the understanding of the underlying mechanism of anti-PD-1/PD-L1 immunotherapy and paving the way for clinical application of ICIs in AML.

In Vitro Study of the Anti-inflammatory and Antifibrotic Activity of Tannic Acid-Coated Curcumin-Loaded Nanoparticles in Human Tenocytes

“…The TA-coated NPs showed no increase in concentration-related toxicity on human tenocytes, maintaining the cell viability at around 80%, whereas in KG-1, the toxicity is dose-dependent (Figure A,B). This can be explained as TA promotes the downregulation of P3K-AKT, an important pathway for the proliferation of these tumor cells involved in acute myelogenous leukemia . Therefore, considering the cell viability of TA-coated NPs, we decided to test in vitro the concentration of 100 μg/mL, excluding higher concentrations that may cause cell toxicity.…”

“…This can be explained as TA promotes the downregulation of P3K-AKT, 40 an important pathway for the proliferation of these tumor cells involved in acute myelogenous leukemia. 41 Therefore, considering the cell viability of TA-coated NPs, we decided to test in vitro the concentration of 100 μg/mL, excluding higher concentrations that may cause cell toxicity.…”

Aberrant promoter hypermethylation of miR-335 and miR-145 is involved in breast cancer PD-L1 overexpression

“…The findings in other human tumors were in accordance with these results. In human AML cancer, the PD-L1 expression level was linked to a high number of cancer cells that were dividing 57 , and it has been shown that too much PD-L1 expression makes tumor cells grow 58 . Additionally, suppressing the expression of PD-L1 in gastric cancer cells could significantly increase apoptosis and reduce invasion, migration, and cell proliferation 59 .…”

TFAP2A promotes cervical cancer via a positive feedback pathway with PD‑L1

“…PD-L1/ITGB6/STAT3 signaling axis regulates bladder cancer cell proliferation, glucose metabolism and chemotherapy resistance ( 51 ). PD-L1 regulates the proliferation and apoptosis of AML cell lines through the PI3K/AKT signaling pathway ( 52 ). However, PI3K-AKT pathway can affect the expression of TFAP2A ( 53 ), suggesting that PI3K-AKT pathway may be a key mediator in PD-L1 regulation of TFAP2A, which is interesting and worthy of further exploration.…”